Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
In myocardial fibrosis, heart muscle is replaced by fibrous or scar tissue. This can interfere with the flexibility of the heart muscle. It can lead to a decrease in function and, eventually, to overt heart failure
In Australia, congestive cardiac failure affects one percent of the general population and three to five percent of those aged over 65, rising to ten to twenty percent of the population aged 80 or over.
Congestive cardiac failure is the most common cause of hospital admission in adult medicine. The annual mortality in admitted patients varies from 10 to 20% in those with mild to moderate symptoms to 40 to 60% in those with severe heart failure. The impact of these admissions and the cost to the community is such that at least two State Governments in Australia have funded programs to improve the management of heart failure. However, these are late stage programs which, while they may curtail admissions in patients with established severe disease, do not address underlying mechanisms. Thus there is a substantial need to reduce or prevent admissions and especially to prevent and/or reverse myocardial fibrosis and its progression, ultimately to the end stage.
The pathologic basis underlying congestive cardiac failure is the development of myocardial fibrosis. This commences as perivascular fibrosis and then extends into the interstitium, becoming more generalised, and resulting in diastolic dysfunction and/or eventually, overt heart failure. There have been numerous studies on humans and animals and these have suggested various factors relevant to myocardial fibrosis, including genetic predisposition, ischaemic heart disease, hypertension, nitric oxide deficiency, oxidative stress, dietary salt intake and various other factors.
In a study of the effect of low, intermediate or high sodium diets fed to rats, the degree of myocardial fibrosis increased with increasing dietary sodium intake. It was found that there was a negative correlation between the concentration of vasoactive intestinal peptide (VIP) in the heart and the degree of myocardial fibrosis (Experimental Physiology (2002) 87.5, 539-546). This study suggested that the decrease in myocardial VIP concentration may play a pathogenic role in the development of myocardial fibrosis.
Vasoactive intestinal peptide (VIP) was first purified in or around the mid-1970's and then synthesised.
U.S. Pat. No. 4,939,224 discusses numerous and varied biological activities of VIP. These include smooth muscle relaxation, inducement of vasodilatation, stimulation of intestinal secretion of water and electrolytes, neuroregulation, stimulation of the production of pancreatic juice and inhibition of gastric acid secretion. However, there are significant deleterious side effects, including hypotension, tachycardia and flushing.
Because VIP was known to exert vasodilatory action and positive ionotropic effect on the heart, its role in myocardial ischaemia was examined (19: J Pharmacol Exp Ther 1994 February; 268(2):952-8). The study was conducted on isolated rat heart. The study found that a significant amount of VIP was released from the ischaemic reperfused heart. In a follow up experiment, the isolated rat heart was perfused with VIP, ischaemia was induced and then the coronary flow was terminated, followed by reperfusion. The study indicated a significant improvement of myocardial function by VIP, evidenced by enhanced left ventricular functions and coronary flow and the reduction of tissue injury.
A study was carried out on isolated trabeculae from the right atrium and left ventricle of human hearts (Clinical Science (2001) 101, 637-643). The hearts were taken from previously healthy individuals who had died from cerebrovascular accidents or head trauma. The study found that VIP had a direct positive ionotropic effect in both the atria and the ventricles of the human heart.
In the study referred to above (Experimental Physiology (2002) 87.5, 529-546), the experiments were conducted on hearts removed from rats treated with sodium diets. This in vitro study found that there was a significant correlation between decreasing myocardial VIP concentration and increasing degree of myocardial fibrosis in the heart. This suggested that VIP depletion in the heart may play a role in the development of fibrosis.
Despite the results of the in vitro studies, it had been found previously that injected VIP was not taken up by the normal heart (Gastroenterology (1979) 77.1, 55-60). The inability of the normal heart to take up injected VIP, indicated that VIP had no role as an effective therapeutic for treatment or prevention of myocardial fibrosis.
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.